SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

One-Alpha® Drops.

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Alfacalcidol 2 micrograms/ml

3. PHARMACEUTICAL FORM

Oral drops, solution

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

One-Alpha^® is indicated in all conditions where there is a disturbance of calcium metabolism due to impaired 1-a hydroxylation such as when there is reduced renal function. The main indications are:

a)    Renal osteodystrophy

b)    Hyperparathyroidism (with bone disease)

c)    Hypoparathyroidism

d)    Neonatal hypocalcaemia

e)    Nutritional and malabsorptive rickets and osteomalacia

f)    Pseudo-deficiency (D-dependent) rickets and osteomalacia

g)    Hypophosphataemic vitamin D resistant rickets and osteomalacia

4.2    Posology and method of administration

One-Alpha^® Drops should be administered orally, using the integral dropper. One drop = 0.1 microgram.

Initial dose for all indications:

Adults:

Dosage in the elderly:

Neonates and premature infants: Children under 20 kg bodyweight:

Children over 20 kg bodyweight:

Half-drop doses should be rounded up to the next whole number of drops.

The dose of One-Alpha^® should be adjusted thereafter to avoid hypercalcaemia according to the biochemical response. Indices of response include plasma levels of calcium (ideally corrected for protein binding), alkaline phosphatase, parathyroid hormone, as well as radiographic and histological investigations.

Plasma levels should initially be measured at weekly intervals. The daily dose of One-Alpha® may be increased by increments of 0.25 - 0.5 microgram. When the dose is stabilised, measurements may be taken every 2 - 4 weeks.

Most adult patients respond to doses between 1 and 3 micrograms per day. When there is biochemical or radiographic evidence of bone healing, (and in hypoparathyroid patients when normal plasma calcium levels have been attained), the dose generally decreases. Maintenance doses are generally in the range of 0.25 to 1 microgram per day. If hypercalcaemia occurs, One-Alpha® should be stopped until plasma calcium returns to normal (approximately 1 week) then restarted at half the previous dose.

(a) Renal bone disease:

Patients with relatively high initial plasma calcium levels may have autonomous hyperparathyroidism, often unresponsive to One-Alpha^®. Other therapeutic measures may be indicated.

Before and during treatment with One-Alpha^®, phosphate binding agents should be considered to prevent hyperphosphataemia. It is particularly important to make frequent plasma calcium measurements in patients with chronic renal failure because prolonged hypercalcaemia may aggravate the decline of renal function.

(b) Hyperparathyroidism:

In patients with primary or tertiary hyperparathyroidism about to undergo parathyroidectomy, pre-operative treatment with One-Alpha^® for 2-3 weeks alleviates bone pain and myopathy without aggravating pre-operative hypercalcaemia. In order to decrease post-operative hypocalcaemia, One-Alpha^® should be continued until plasma alkaline phosphatase levels fall to normal or hypercalcaemia occurs.

(c) Hypoparathyroidism:

In contrast to the response to parent vitamin D, low plasma calcium levels are restored to normal relatively quickly with One-Alpha®. Severe hypocalcaemia is corrected more rapidly with higher doses of One-Alpha® (eg 3-5 micrograms) together with calcium supplements.

(d)    Neonatal hypocalcaemia:

Although the normal starting dose of One-Alpha® is 0.05-0.1 microgram/kg/day (followed by careful titration) in severe cases doses of up to 2 microgram/kg/day may be required. Whilst ionised serum calcium levels may provide a guide to response, measurement of plasma alkaline phosphatase activity may be more useful. Levels of alkaline phosphatase approximately 7.5 times above the adult range indicates active disease.

A dose of 0.1 microgram/kg/day of One-Alpha® has proven effective as prophylaxis against early neonatal hypocalcaemia in premature infants.

(e)    Nutritional and malabsorptive rickets and osteomalacia:

Nutritional rickets and osteomalacia can be cured rapidly with One-Alpha^®. Malabsorptive osteomalacia (responding to large doses of IM or IV parent vitamin D) will respond to small doses of One-Alpha®.

(f)    Pseudo-deficiency (D-dependent) rickets and osteomalacia:

Although large doses of parent vitamin D would be required, effective doses of One-Alpha^® are similar to those required to heal nutritional vitamin D deficiency rickets and osteomalacia.

(g)    Hypophosphataemic vitamin D-resistant rickets and osteomalacia:

Neither large doses of parent vitamin D nor phosphate supplements are entirely satisfactory. Treatment with One-Alpha^® at normal dosage rapidly relieves myopathy when present and increases calcium and phosphate retention. Phosphate supplements may also be required in some patients.

4.3 Contraindications

Hypercalcaemia, metastatic calcification.

Hypersensitivity to alfacalcidol or any of the other ingredients.

4.4 Special warnings and precautions for use

One-Alpha® should be used with caution for:

•    patients being treated with cardioactive glycosides or digitalis as hypercalcaemia may lead to arrhythmia in such patients

•    patients with nephrolithiasis

During treatment with One-Alpha® serum calcium and serum phosphate should be monitored regularly especially in children, patients with renal impairment and patients receiving high doses. To maintain serum phosphate at an acceptable level in patients with renal bone disease a phosphate binding agent may be used.

Hypercalcaemia may appear in patients treated with One-Alpha^®, the early symptoms are as follows:

•    polyuria

•    polydipsia

•    weakness, headache, nausea, constipation

•    dry mouth

•    muscle and bone pain

•    metallic taste

Hypercalcaemia can be rapidly corrected by stopping treatment until plasma calcium levels return to normal (in about one week). One-Alpha^® treatment may then be restarted at a reduced dose (half the previous dose).

4.5    Interaction with other medicinal products and other forms of interaction

Patients taking barbiturates or anticonvulsants may require larger doses of One-Alpha® to produce the desired effect due to the induction of hepatic detoxification enzymes.

Use with caution in patients being treated with thiazide diuretics as they may have an increased risk of developing hypercalcaemia.

4.6    Pregnancy and lactation

There are no adequate data from the use of alfacalcidol in pregnant women. Animal studies are insufficient with respect to effects on pregnancy. The potential risks for humans are unknown. Caution should be taken when prescribing to pregnant women as hypercalcaemia during pregnancy may produce congenital disorders in the offspring.

Although it has not been established, it is likely that increased amounts of 1,25-dihydroxyvitamin D will be found in the milk of lactating mothers treated with One-Alpha^®. This may influence calcium metabolism in the infant.

4.7    Effects on ability to drive and use machines

One-Alpha® has no or negligible influence on the ability to drive or use machines.

4.8    Undesirable effects

The most frequently reported undesirable effects are hypercalcaemia and various skin reactions. Hypercalcaemia can be rapidly corrected by stopping treatment until plasma calcium levels return to normal (about 1 week). One-Alpha^® treatment may then be re-started at half the previous dose.

Based on data from post-market use the total undesirable effect ‘reporting rate’ is rare or very rare being approximately 1:10,000 patients treated.

• Metabolism and Nutrition Disorders

Hypercalcaemia

Hyperphosphataemia

•    Skin and Subcutaneous Tissue Disorders

Pruritus

Rash

Urticaria

•    Renal and Urinary Disorders

Nephrocalcinosis Renal impairment

4.9    Overdose

Hypercalcaemia is treated by suspending the administration of One-Alpha^®.

In severe cases of hypercalcaemia general supportive measures should be undertaken. Keep the patient well hydrated by i.v. infusion of saline (force diuresis), measure electrolytes, calcium and renal function indices; assess electrocardiographic abnormalities, especially in patients on digitalis. More specifically, treatment with glucocorticosteroids, loop diuretics, bisphosphonates, calcitonin and eventually haemodialysis with low calcium content should be considered.

5    PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Alfacalcidol is converted rapidly in the liver to 1,25- dihydroxyvitamin D. This is the metabolite of vitamin D which acts as a regulator of calcium and phosphate metabolism. Since this conversion is rapid, the clinical effects of One-Alpha® and 1,25 dihydroxyvitamin D are very similar.

Impaired 1-a hydroxylation by the kidneys reduces endogenous 1,25-dihydroxyvitamin D production. This contributes to the disturbances in mineral metabolism found in several disorders, including renal bone disease, hypoparathyroidism, neonatal hypocalcaemia and vitamin D dependent rickets. These disorders, which require high doses of parent vitamin D for their correction, will respond to small doses of One-Alpha®.

The delay in response and high dosage required in treating these disorders with parent vitamin D makes dosage adjustment difficult. This can result in unpredictable hypercalcaemia which may take weeks or months to reverse. The major advantage of One-Alpha^® is the more rapid onset of response, which allows a more accurate titration of dosage. Should inadvertent hypercalcaemia occur it can be reversed within days of stopping treatment.

5.2. Pharmacokinetic properties

In patients with renal failure, 1-5pg/day of 1 a-hydroxyvitamin D (1a-OHD3) increased intestinal calcium and phosphorus absorption in a dose-related manner. This effect was observed within 3 days of starting the drug and, conversely, it was reversed within 3 days of its discontinuation.

In patients with nutritional osteomalacia, increases in calcium absorption were noted within 6 hours of giving 1 pg 1a-OHD3 orally and usually peaked at 24 hours. 1a-OHD3 also produced increases in plasma inorganic phosphorus due to increased intestinal absorption and renal tubular re-absorption. This latter effect is a result of PTH suppression by 1a-OHD3. The effect of the drug on calcium was about double its effect on phosphorus absorption.

Patients with chronic renal failure have shown increased serum calcium levels within 5 days of receiving 1a-OHD3 in a dose of 0.5 - 1.0 pg/day. As serum calcium rose, PTH levels and alkaline phosphatase decreased toward normal.

5.3. Preclinical safety data

There are no pre-clinical data of relevance to the prescriber which are additional to that already included in other sections of the SPC.

6. PHARMACEUTICAL PARTICULARS 6.1. List of excipients

Ethanol, polyoxyl 40 hydrogenated castor oil, methylparahydroxybenzoate, citric acid monohydrate, sodium citrate, sorbitol, dl-a-tocopherol and purified water.

6.2. Incompatibilities

None known.

6.3 Shelf life

3 years.

After opening, the shelf-life is 28 days when stored at 2- 8°C (in a refrigerator).

6.4 Special precautions for storage

Store at 2-8°C (in a refrigerator). Keep the container in the outer carton.

For storage conditions after first opening of the medicinal product, see section

6.3.

6.5.    Nature and contents of container

Amber glass bottles of 10 ml and 20 ml, with a polyethylene dropping device and a polypropylene screw cap.

6.6.    Instruction for use/handling

None.

7 MARKETING AUTHORISATION HOLDER

LEO Laboratories Limited

Horizon

Honey Lane

Hurley

Maidenhead

Berkshire

SL6 6RJ

UK

8. MARKETING AUTHORISATION NUMBER

PL 00043/0207

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE

AUTHORISATION 3 March 2000

10 DATE OF REVISION OF THE TEXT

02/12/2013